VIA ARYNE ANNULATION †,56
2.3.2 Synthesis of Isoquinolines via Aryne Annulation
In an effort to suppress the suspected mode of side reactivity and thus avoid further
product mixtures, we set out to examine alternative nitrogen substituents that would
decrease the nucleophilicity of the enamine π-system by sequestering the nitrogen lone
pair. We considered an acetyl group due to its increased electron withdrawing potential
relative to the tert-butyl carbamate. N-Boc dehydroalanine methyl ester (166) was
therefore replaced with its N-acetyl congener (175) and the aryne annulation was
attempted with 2-(trimethylsilyl)phenyl triflate (71) (Scheme 2.11). However, instead of
isolating the expected N-acetyl indoline ester (177), we were surprised to find that methyl
1-methylisoquinoline-3-carboxylate (176 ) was the only product generated. This
interesting structure most likely arises through nucleophilic addition of the enamine
carbon to benzyne (1), followed by intramolecular addition of the aryl anion to the
carbonyl of the intermediate N-acetylimine (178). Subsequent aromatization through the
loss of an equivalent of water from dihydroisoquinoline 179 would then produce the
isoquinoline.
69If this mechanism is indeed operative, it would indicate that exchanging
the carbamate for the acetamide had little effect on the electronic properties of the
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
58 enamine, and instead only provided a carbonyl electrophile more reactive than the N- carbamoyl imine (174) to quench the intermediate aryl anion.
Scheme 2.11. Unexpected formation of an isoquinoline through an alternative aryne annulation
TMS
OTf NHAc
OMe O +
71 175
NHAc OMe O
1 175
TBAT
THF, 23 °C N
OMe O
NAc CO2Me
not observed
NH OMe O
O
N OMe O
HO
178 179
176
– H2O
177
Having discovered this unexpected mode of orthogonal reactivity, we undertook a screen of reaction conditions to optimize the yield of isoquinoline 176 (Table 2.3).
Caesium fluoride once again performed admirably as a fluoride source (entries 1–6), generating the desired isoquinoline in up to 65% yield at room temperature (entry 3).
Potassium fluoride also proved effective, although less so than caesium fluoride (entries
7–9). As was the case in the previous indoline synthesis, however, TBAT was again
identified as the optimal fluoride source (entries 11–14). Using this reagent, isoquinoline
176 could be isolated in up to 87% yield within 6 hours when the reaction was performed
in THF at a slightly lower concentration (0.01 M) (entry 14).
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
59
Table 2.3. Optimization of reaction conditions for isoquinoline synthesis via aryne annulation
yield entry
1 2 3
6 5
TMS
OTf
aryne
equivalents fluoride source
fluoride
equivalents conc. (M) temp. (°C)
8 9 10 11 7
12a 13
4
fluoride source solvent, temp
solvent NH
O OMe
175
71 176
+
14
KF / 18-C-6 KF / 18-C-6 KF / 18-C-6
25 25
25
25 25 40
57%
61%
30%
36%
34%
40%
0.2 0.1
0.1
0.2 0.2 0.2 2.0
1.5 1.5
1.5
2.0 1.5
2.0 3.0
2.0 3.0 2.0 2.0 CsF
CsF
CsF
25 50%
0.2
1.25 CsF 2.0
25 0%
0.2
1.25 CsF 2.0
25 65%
0.2
2.0 CsF 2.0
MeCN
THF MeCN MeCN MeCN MeCN
THF THF THF
25 13%
0.2
2.0 2.0 CH2Cl2
25 71%
0.2
2.0 2.0 CH2Cl2
120 56%
0.2
2.0 2.0 CH2Cl2
25 87%
0.01
2.0 TBAT 2.0 THF
TBAT TBAT TBAF
40 77%
0.2
2.0 TBAT 2.0 THF
O N
O OMe
a Reaction performed in a microwave reactor.
From a synthetic standpoint, the isoquinoline carbon framework provides a number of
sites for introduction of synthetic functionality, and furthermore, our aryne annulation
technology enables a convergent approach to the assembly of these functionalized
derivatives. In particular, isoquinolines bearing substitution at carbons 1, 3, and 4 can be
prepared through manipulation of the dehydroamino ester, while substitution at carbons
5–8 originate from manipulation of the aryne. To systematically verify the capabilities of
this approach, we began by preparing a series of N-acyl dehydroalanine methyl esters
(180) for the synthesis of C(1)-substituted isoquinolines (181) (Table 2.4). To our
delight, the reaction proved quite tolerant to the introduction of a wide variety of
functionality at this position, ranging from linear and branched alkyl chains (entries 1–4)
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
60 to aryl groups (entries 5 and 6) and even heteroatom-functionalized sidechains (entries 7–9). Importantly, the carbon atom α to the amide carbonyl can be introduced in several different oxidation states—from alkane (entries 1–5) to alcohol (entries 6 and 8) to carboxylic acid (entries 7 and 9)—without detriment to the product yield.
Table 2.4. Synthesis of C(1)-substituted isoquinolines via aryne annulationa
R = Me R = n-Bu
R = c-Hex
R = CF3
R = CH2OMe R = CO2Me R = Bn R = Ph R = i-Pr 180a, 180b,
180d,
180g, 180h, 180i, 180e, 180f, 180c,
yield entry
1 2 3
6 5
TMS
OTf
8 9 7 4
NH O
OMe
180
71 181
+
87%
76%
65%
57%
68%
51%
72%
55%
66%
O R
N R
O OMe
N-acyl enamine (180) isoquinoline (181) TBAT (2 equiv)
THF (0.01 M)
23 °C, 6 h 1
R = Me R = n-Bu
R = c-Hex
R = CF3
R = CH2OMe R = CO2Me R = Bn R = Ph R = i-Pr 176, 181a,
181c,
181f, 181g, 181h, 181d, 181e, 181b,
3 4 5 6
7 8
a Reaction performed with 2.0 equiv ortho-silyl aryl triflate 71 relative to enamine 180.
Next, we turned our attention to the effect of aryne substitution on reactivity. Using
methyl 2-acetamidoacrylate (175 ) as a model N-acyl enamine, we tested a pair of
monosubstituted arynes displaying functionality ortho and meta to the reactive aryne
triple bond (108 and 183) as well as three disubstituted arynes (155, 184, and 185) (Table
2.5). All five substrates performed well, providing the expected isoquinolines (182a–f)
in good yield. Notably, both electron-rich (entries 1–4) and electron-deficient (entry 5)
arynes successfully underwent aryne annulation. Not surprisingly, difluoroaryne 185
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
61 proved to be the most productive substrate, most likely due to the increased reactivity provided by the inductively withdrawing halide substitution. We were also pleased to find that ortho-methoxy aryne 108 generated only one product isomer (182a) derived from the expected mode of nucleophilic attack meta to the ether. On the other hand, the meta- methyl aryne (183) provided a 1:1 mixture of isomeric isoquinolines (182b and c),
Table 2.5. Aryne substrate scope in isoquinoline synthesis
yield entry
1
2
3
TMS
OTf
4
NH O
OMe
175
168 182
+
66%
59%
60%
63%
O N
O OMe
substrate product
TBAT (2 equiv) THF (0.01 M)
23 °C, 6 h
N O
OMe
R R
OMe TMS OTf
OMe
N O
OMe OTf
TMS
N O + OMe
N O
OMe TMS
OTf
5 78%
O O
O O
N O
OMe TMS
OTf MeO
MeO
MeO
MeO
N O
OMe TMS
OTf F
F
F
F
108 182a
183 182b
155 182d
184 182e
185 182f
182c 1 : 1
a Reaction performed with 2.0 equiv ortho-silyl aryl triflate 168 relative to enamine 175.
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
62 demonstrating the weak directing effect afforded by inductive donation from alkyl substituents.
Having confirmed that this orthogonal method of aryne annulation was capable of constructing several highly substituted isoquinoline esters, we began to reconsider the structural requirements for the enamine substrates in terms our proposed mechanism.
Dehydroamino esters were originally selected because they contained both a nitrogen nucleophile and a conjugate acceptor amenable to the preparation of indolines. We continued to employ these compounds after discovering that the N-acyl derivatives underwent a separate annulation to form isoquinolines. However, the mechanism we envision to lead to the formation of isoquinolines draws no benefit from the presence of the vestigial ester. We therefore set out to determine whether removing or replacing this group would have any effect upon reactivity.
The first substrates we tested were acetamides 186a and b, derivatives of 3-pentanone
and pinacolone, respectively.
70Gratifyingly, both compounds produced the
corresponding isoquinolines (187a and b) in very good yield and in far less time than
required to form isoquinoline esters 181a–i (entries 1 and 2).
71This increase in rate lends
credence to our hypothesis that the ester exerts a retarding effect upon the reactivity of
the dehydroamino esters (180a–i) by removing electron density from the enamine carbon
terminus. To further our investigation of N-acyl enamines, we prepared cyclic enamines
186c–f, which furnished a series of tricyclic isoquinolines (187c–f) upon aryne
annulation (entries 3–6). Importantly, it was possible to incorporate carbonyl
functionality both within the ring (entry 5) and pendant to it (entry 6) without affecting
reactivity.
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
63
Table 2.6. N-Acyl enamine substrate scopea
yield entry
1 2
3
6 5
TMS
OTf
4
R2 NH
186
71 187
+
72%
83%
67%
66%
71%
66%
O N
R2
substrate product
TBAT (2 equiv) THF (0.01 M), 23 °C
0.25–2 h
R1 R1
R2
NH
186a, R1 = Et, R2 = Me O
R1
186b, R1 = H, R2 = t-Bu N R2 R1
187a, R1 = Et, R2 = Me 187b, R1 = H, R2 = t-Bu
NH
186c, n = 1, X = H2
O
186d, n = 2, X = H2
N
187c, n = 1, X = H2 187d, n = 2, X = H2
X X
n n
186e, n = 2, X = O 187e, n = 2, X = O
NH
O CO2Me N
CO2Me
186f 187f
a Reaction performed with 2.0 equiv ortho-silyl aryl triflate 71 relative to enamine 186.
In order to test the lower limit of substitution on the N-acyl enamine substrate structure, we attempted an aryne annulation using N-vinyl acetamide (188), a compound lacking substitution at the carbon atom attached to nitrogen (Scheme 2.12).
Unfortunately, instead of isolating the desired 1-methylisoquinoline, the substrate underwent exclusive arylation at the carbon terminus to produce styrene 190 as an inseparable mixture of olefin isomers in 77% yield.
72One possible explanation for this phenomenon is a rotation about the C(α)–N bond of 188, leading to an “s-trans-like”
conformation.
73This conformer would then be capable of undergoing an ene reaction
with benzyne (1) to generate intermediate N-acetyl imine 189. Tautomerization to
regenerate the enamine would then yield the observed styrene (190).
74Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
64 The arylation of N-vinyl acetamide through an “s-trans-like” conformation would indicate a need for some form of substitution at C(α) in order to induce a preference for the “s-cis-like” conformation through steric interactions between the acetyl group and the C(α) substituent. To gain a better understanding of the relationship between enamine substitution and conformational preference, we calculated the ground state energies of each of the rotational conformers of N-vinyl acetamide (188), N-(2-propenyl)acetamide (191 ), and N-(3,3-dimethyl-2-butenyl)acetamide (186b).
75In accordance with the postulated ene mechanism of C-arylation, the “s-trans-like” conformation of N-vinyl acetamide is preferred by 2.3 kcal
·mol
–1. The introduction of a methyl group at C(α ) lowers the energy difference to 0.4 kcal
·mol
–1, only slightly in favor of the “s-trans-like”
conformation. Conversely, the presence of a tert-butyl group at C(α) produces a strong preference for the “s-cis-like” conformation (5.8 kcal
·mol
–1), which helps to explain the observation that 186b reacts faster than any other substrate we have tested to date.
71Scheme 2.12. Arylation of N-vinyl acetamide
NH O
s-trans-186b NH
O
s-trans-191 TMS
OTf
NH
s-cis-188 71
+ O
TBAT (2 equiv) THF, 23 °C
NH O
NH O
s-cis-188
NH O
s-trans-188 – 2.3
kcal•mol–1
H N O
ene
N O
H 2 equiv
+
1 s-trans-188 189 190, 77% yield
NH O
s-cis-191
NH O
s-cis-186b – 0.4
kcal•mol–1
+ 5.8 kcal•mol–1 α
β
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
65 2.3.3 Total Synthesis of Papaverine
Having developed this powerful condensation reaction for generating isoquinolines, we sought to demonstrate its utility in a rapid total synthesis of papaverine
76(197), a clinically used non-narcotic antispasmotic agent that is a biosynthetic precursor to several of the pavine alkaloids and one of the four major constituents of opium (Scheme 2.13).
77Our synthesis began with the condensation of homoveratric acid (192) and serine methyl ester•HCl (193), followed by elimination to provide N-acyl enamine 195.
78In the key annulation, enamide 195 underwent dehydrative addition to the aryne generated from ortho-silyl aryl triflate 184 to furnish isoquinoline ester 196 in 70% yield. Lastly, saponification and thermal decarboxylation
79afforded papaverine (197) in 29% overall yield. Our synthesis totals three steps from commercially available materials, which marks the shortest synthesis of this important alkaloid reported to date.
80,81Scheme 2.13. Total synthesis of papaverine
OH O
OMe
OMe
192
NH O
OMe
OMe
195 O
OMe
N
OMe
OMe 196
O MeO OMe
MeO N
OMe
OMe Papaverine (197) MeO
MeO (COCl)2, DMF, CH2Cl2
then Et3N,
HO CO2Me NH2•HCl
TMS
OTf MeO
MeO
193
TBAT THF, 23 °C (70% yield)
184
LiOH•H2O, THF / H2O then HCl then Δ (neat)
(61% yield) 23 °C
(67% yield)
NH O
OMe
OMe 194
O OMe O
MeO O MeO
50 °C – 192 (1 equiv)
(2 equiv)
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
66 2.3.4 An Alternative Approach to the Synthesis of Isoquinolines and
Benzocyclobutenes via Aryne Annulation
Shortly after our communication detailing the development of two orthogonal aryne annulation methods, Blackburn and Ramtohul at Merck Frosst reported a similar approach to the synthesis of isoquinoline esters (181) (Table 2.7).
82However, in addition to this heterocycle, the authors also noted the formation of a second annulation product—a benzocyclobutene amino ester (198). In contrast to the isoquinoline, which forms through a formal dehydrative [4 + 2] addition, the benzocyclobutene is the product
Table 2.7. Ramtohol – Isoquinoline and benzocyclobutene synthesis via aryne annulation
180a 180b
180d
180g 180h 180i 180e 180f 180c
yield (XX) entry
1
2
3
6 5
TMS
OTf
8
9 7 4
NH O
OMe
180
71 181
+
64%
59%
62%
69%
56%
42%
51%
66%
64%
O R
N R
O
OMe MeO2C
NH R O
198 +
CsF (2.5 equiv) MeCN, 18h
yield (XX) 24%
21%
18%
24%
22%
12%
21%
25%
22%
180j 180k 11
10 66%
42%
22%
11%
MeO O O
F
O
O F
H
Me
R
181a 181b
181d
181g 181h 181i 181e 181f 181c
181j 181k
198a 198b
198d
198g 198h 198i 198e 198f 198c
198j 198k
a Reaction performed with 1.25 equiv ortho-silyl aryl triflate 71 relative to enamine 180.
Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation